Alzheimer's disease (AD) is a progressive, fatal neurode generative disorder of the elderly. AD shows a slowly progressive mental deterioration with failure of memory, disorientation and confusion leading to profound dementia. There are several histologic features, but two are striking. First, argyrophilic plaques comprised of the amyloidogenic A.beta. fragment of amyloid precursor protein (APP) are scattered throughout the cerebral cortex and hippocampus. Second, neurofibrillary tangles are found in pyramidal neurons predominantly located in the neocortex, hippocampus, and nucleus basalis of Meynert. There are other changes, also. Granulo-vacuolar degeneration in the pyramidal cells of the hippocampus has been considered by some to be more specific for AD than plaques or neurofibrillary tangles. Finally, there is neuronal loss and gliosis in the cerebral cortex and hippocampus.
There are patients with dementia who lack the pathologic features of AD (and by definition have a different disease), and conversely, there are individuals with many of the pathologic features of AD who were not demented prior to death. The diagnosis of AD requires that both the clinical and the pathological features characteristic for the disease be present in the patient; the diagnosis cannot be made with certainty from either clinical or pathological features alone. Whether neural dysfunction and clinical abnormalities precede the development of these pathologic features, particularly the amyloid plaques and neurofibrillary tangles, is unknown.
The clinical manifestations of AD predict the regions of affected brain structures in the forebrain, including the cerebral cortex, hippocampus, amygdala, and parahippocampal gyri. These regions are known as the cortico-limbic areas of the brain. The basal ganglia is spared, as is the hindbrain, including the cerebellum, the pontine and the medullary nuclei. Within the cerebral neocortex, the primary cortical areas area relatively spared, which corresponds to the relative clinical sparing of basic motor and sensory cortical functions.
Transgenic mice harboring APP transgenes have been described; however, transgene product expression falls considerably short of endogenous levels of APP (total APP levels in the other transgenic mice have not exceeded 150% of endogenous levels), and fails to generate a disease phenotype with a progressive neurobehavioral disorder accompanied by pathology in the cortico-limbic regions of the brain. In these other transgenic mice, there have been no signs of a progressive neurologic disorder or of neuropathologic changes in the brain which may be regarded as evidence of a true neurologic disease.
Preamyloid APP plaques have been observed in some transgenic mice. However, preamyloid APP plaques are not necessarily indicative of a disease, since they are routinely observed in human brain regions, such as the cerebellum, which are devoid of other signs of pathology or clinical manifestations. Increased APP immunoreactivity located within vesicular structures in hippocampal neurons of transgenic mice has been reported, but the significance of this immunoreactivity is unclear since the mice exhibited neither a progressive neurobehavioral disorder nor evidence of true neuropathology.
It therefore is of interest to develop a transgenic nonhuman mammalian model for AD wherein the animal develops a progressive neurologic disease of the cortico-limbic brain resembling AD, both clinically and pathologically (e.g. the gliosis and the specific brain regions affected). It also is desirable that the animal develops neurologic disease within a fairly short period of time from birth, facilitating the analysis of multigenerational pedigrees. The model can be used to study the pathogenesis and treatment of AD since there is a distinct and robust clinical and pathologic phenotype to examine and score.